Cigarette smoking is the leading cause of lung cancer. However, only a small portion of the patients who are smokers ever develop lung cancer. Furthermore, more and more patients who have never smoked also develop lung cancer. The cause of lung cancer for those who have never smoked is unknown. To address this question, we collaborated with Dr. Neil Caporaso and his colleagues at DCEG and performed extensive analysis to examine gene expression profiles using paired lung cancer and normal samples from patients who are current, past, and never smokers. Analysis of gene expression changes in lung tumors from patients with different smoking status revealed that 1) although clinically distinguishable, a majority of lung cancers from non-smoking patients most likely developed via a different molecular mechanism from those that developed from patients who had smoked. 2) Lung tumors from past smokers are molecularly similar to those of the current smokers and most likely have occurred as a result of the damages caused by smoking. We observed that at the molecular level, distinctly different molecular pathways appeared to be involved in tumors of smoking or nonsmoking patients. We are focusing our study on genes that are uniquely associated with lung tumors from non-smoking patients to determine the etiology of these lung cancers. We also analyse genetic mutations in candidate genes to identify those that might involved in the the development of lung cancer from non-smoking patients.